Multi-omics reveals colonic lesion formation via mucus accumulation by the TNF-α/IL-1β/PGE2 axis in Cronkhite–Canada syndrome

Cronkhite–Canada syndrome (CCS) is a rare non-inherited hamartomatous polyposis syndrome with unknown pathogenesis. To investigate this, we performed single-cell RNA sequencing, spatial in situ sequencing, and bulk RNA-seq on colon biopsies from CCS patients and healthy controls, along with cytokine profiling and organoid/cell line experiments. Multi-omics analysis revealed goblet cell hyperplasia and increased mucin secretion, spatially associated with an inflammatory niche consisting of TNF⁺ Th1 cells, FCN1 + monocytes, and IL1B + macrophages, all highly active in CCS. Functional assays showed that low-dose TNF-α drives monocyte differentiation into IL-1β-secreting macrophages, while IL-1β induces epithelial PGE 2 production, which further amplifies IL-1β secretion, establishing a self-reinforcing loop. An independent cohort confirmed mild elevation of peripheral TNF-α and TNF/IL-1 pathway activation. These findings delineate a pathogenic circuit linking adaptive immune dysregulation, innate remodeling, and epithelial changes, positioning the TNF-α/IL-1β/PGE 2 axis as the driver of mucus accumulation and hamartoma formation, offering new potential therapies for CCS. Key features distinguishing Cronkhite–Canada syndrome (CCS) hamartomatous polyps from healthy intestinal tissues and crosstalk among CD4 + T-helper 1 TNF + cells, FCN1 + monocytes, IL1B + macrophages, and altered epithelial lineage establish a unique immune microenvironment in CCS. This interaction network drives the accumulation of mucus and remodeling of epithelial lineages via paracrine signaling (e.g., TNF-α/IL-1β/PGE 2 axis), collectively forming a pathogenic triad that underpins the development of CCS lesions.